Funded Research

June 15, 2008: The Liddy Shriver Sarcoma Initiative is funding a 1-year $50,000 research study, "Characterization of WWOX tumor suppressor gene in osteosarcoma," to researchers at Tianjin Cancer Hospital in China and Institute and the University of Texas M.D. Anderson Cancer Center in Texas. This study was made possible, in part, by several generous donations from Herbert Blodgett in loving memory of his wife, Merril, by donations from Una O'Hagen in memory of her son Sean Keane, donations from the Kleftis family in memory of Gregory.

Led by Jilong Yang, M.D., Ph.D in China and his collaborator Wei Zhang, Ph.D. at M.D. Anderson Cancer Center, this study is focused on improving our understanding of the molecular mechanisms of osteosarcoma development by determining if the WWOX gene is a key tumor suppressor gene and a new target for gene therapy development for osteosarcoma. WWOX (WW domain containing oxidoreductase) is a tumor suppressor gene spanning a genomic region of 1.1 Mb located at chromosome 16q23.3-24.1, a region with a high incidence of loss of heterozygosity (LOH) in breast, lung, prostate, and other cancers. WWOX protein contains two WW domains in the NH2-terminal region and a short chain dehydrogenase/reductase (SDR) domain in the central region of the protein.

Thus far, there is no information about WWOX gene in human osteosarcoma. Recently, Aqeilan et al generated a mouse strain with WWOX gene deleted and found spontaneously developed osteosarcoma in juvenile WWOX_/_ mice and lung papillary carcinoma in adult WWOX _/_ mice. In this study, we propose to test the hypothesis that the WWOX gene is an osteosarcoma tumor suppressor gene that is inactivated in human osteosarcoma. We will perform the following experiments in this study.

1. To examine homozygous deletion, loss of heterogeneity (LOH), methylation of WWOX promoter, and mutation of WWOX in osteosarcoma cell lines and patient tumor tissues.

2. To investigate the role of WWOX in cell apoptosis and proliferation by correlating WWOX gene deletion, mutation, and expression status with expression for P73, BAX, Bcl-2, Bcl-xL, casepase-3, casepase-9, Ki-67 and PCNA.

We will use standard molecular and pathological methods including PCR analysis, sequencing, Immunoblotting and immunohistochemistry, methylation-specific PCR (MSP), DHPLC and flow cytometric analysis. The tissue bank of our hospital has accumulated 35 frozen osteosarcoma tissues and there are about 150 paraffin-embedded archival blocks available for this investigation. Our preliminary investigations in human osteosarcoma tissues detected WWOX gene deletion and promoter methylation. These studies support our hypothesis.

You can read more about the approach they are taking in the article, Characterization of WWOX tumor suppressor gene in osteosarcoma, which appears in the June 2008 issue of ESUN.